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Figure 57 Comparison of liposome water (solid lines) to octanol water (dashed lines) lipophilicity pro les for a weak acid, a weak base, and an ampholyte [Avdeef, A, Curr Topics Med Chem, 1, 277 351 (2001) Reproduced with permission from Bentham Science Publishers, Ltd]
occur in the pH regions where charged-species partitioning takes place In Section 47 we noted that octanol water diff(log PN I ) values for simple acids were $4 and for simple bases $3 When it comes to liposome water partitioning, the diff 3 4 rule appears to slip to the diff 1 2 rule This is evident in Figs 57a,b The smaller diffmem values in membrane systems have been noted
log D mem, diff mem, AND THE PREDICTION OF log P SIP FROM log P I mem
for some time, for example, with reported diffmem 0 for tetracaine, 1 for procaine and lidocaine [455], and diffmem 1:45 for tetracaine [424] Miyazaki et al [396] considered diffmem values of 22 for acids and 09 for bases in their study of dimyristoylphosphatidylcholine (DMPC) bilayer dispersions Other studies indicated similar diff values [149,383 386,433 438,441,442] It seems that charged species partition into membranes about 100 times more strongly than suggested by octanol Alcorn et al [433] studied the partitioning of proxicromil (acid: pKa 193, log PN $5, log PI 18 [456]) in MLV liposomes prepared from reconstituted brushoct oct border lipids (slightly negatively charged at pH 74) Membrane partition coef cients were determined by the centrifugation (15 min, 150 kg) method It was observed that in 015 M NaCl background, proxicromil showed a nearly constant log Dmem (30 35)at pH 4 9, which was unexpected, given the pKa However, when the background salt was lowered to 0015 M, the expected curve shape (log Dmem 35 at pH 3 and 15 at pH 9) was observed, similar to that in Fig 57a Interestingly, the researchers took the solutions at pH 8 and titrated them with NaCl and LiCl The log Dmem seen in the 015 M NaCl medium was reestablished by titration (more easily with NaCl than LiCl) The ionic strength dependence can be explained by the Gouy Chapman theory [406,407] The sample concentration (167 mM) was high enough to cause a buildup of negative charge on the surface Without the high 015 M NaCl to shield the surface charge, sample anion-anion electrostatic repulsion on the membrane surface prevented the complete partitioning of the drug, making it appear that log Dmem was lowered The Na titration reduced the surface charge, allowing more anionic drug to partition The fact that the Na titrant is more effective than the Li titrant can be explained by the higher hydration energy of Li , making it less effective at interacting with the membrane surface [400] Incidently, we predict the log PN mem of proxicromil using the relationship in Fig 56 to be $4, in very acceptable agreement with the observed value In well-designed experiments, Pauletti and Wunderli-Allenspach [435] studied the partitioning behavior of propranolol in eggPC at 37 C, and reported log Dmem for pH 2 12 SUVs were prepared by the controlled detergent method The equilibrium dialysis method was used to determine the partition coef cients, with propranolol concentration (10 6 to 10 9 M) determined by liquid scintillation counting The lipid concentration was 52 mM Internal pH of liposomes was checked by the uorescein isothiocyanate method Gradients in pH were dissipated within 5 min after small pH changes in the bulk solution The lipophilicity curve they obtained is very similar in shape to that of tetracaine, shown in Fig 57b The log PN 3:28 and log PSIP 2:76 values indicate diffmem 0:52 mem mem Austin et al [441] reported the partitioning behavior of amlodipine, 5-phenylvaleric acid, 4-phenylbutylamine, and 5-hydroxyquinoline at 37 C in 1 100 mg mL 1 DMPC SUVs The ultra ltration (10 kDa cutoff) with mild (15 kg) centrifugation method was used to determine partition coef cients Sample concentrations were 3 8 10 5 M Most remarkably, diff mem 0:0 was observed for amlodipine A similarly low value of 029 was reported for 4-phenylbutylamine Furthermore, the partitioning behavior was unchanged by ionic strength changes in the interval 00 015 M, seemingly in contradiction to the effect observed by Alcorn and coworkers They proposed that charged molecules associated with the charged head